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Teasdale 2015
Teasdale 2015
pubs.acs.org/OPRD
Regulatory Highlights
INTRODUCTION
Compared to last year, 2015 may seem in comparison quiet in
terms of new regulations; however, across a series of guidance
areas, there has been a concerted reection focused on practical
implementation of the guidelines concerned. In the case for
example of ICH Q3D1 elemental impurities, there have been
a considerable number of symposia and publications centered
on practical implementation, culminating in the continued de-
velopment of training material by the ICH Q3D implementa-
tion group. In June of this year, the nalized ICH Q7 Q&A2
document was published; the content of which and the impli-
cations are explored in more depth later in the review. Similarly,
there have been continued eorts to address the implementa-
tion challenges posed by ICH Q11,3 although there have been
no further public disclosures upon which to comment. 2015 has
also seen the evolution of a working framework for the eagerly
anticipated ICH Q12 Product Life Cycle Management. What
therefore may seem a quiet period ultimately turns out to have Figure 1. Derek predictions versus Leadscope predictions for 801
been an intriguing period; the actual as well as eventual output compounds tested in the Ames assay.
from ongoing developments will ultimately form the basis of
practical implementation for many guidelines integral to drug
A chemist seeking to validate the drug substance process and the
substance development.
in such circumstances expert review signicantly enhanced pre-
dictive performance. Barber et al.8 illustrated what such an expert ELEMENTAL IMPURITIES (EIs)
review may look like when graphically represented (Figure 2).
While such an expert review clearly needs an in-depth knowledge At the end of 2014, immediately after nalization of ICH
of the systems and the methodological basis for their predictions, Q3D,2 ICH took the unprecedented step of immediately
it also requires a detailed knowledge of the underlying chemistry. establishing an implementation working group (IWG) to
Again to stress a point made previously in this review, this must support the roll out of the nalized guideline, recognizing the
therefore involve a chemist in the process. practical challenges faced in its implementation. The primary
Critical to any control strategy is establishing the level that purpose of the IWG is to produce training material to support
must be achieved; this is amplied when addressing mutagenic
impurities where the permitted levels are often very low.
Figure 2. Decision matrix when evaluating two in silico predictions. OOD refers to out of domainthis reecting the inability of the systems
concerned to recognize either the whole or signicant fragments of the molecule.
the process. The material is still under development with no The ICH Q7 Guideline is implemented successfully in the
formal date for nalisation, what is known is that it is likely to regulatory framework by WHO and most authorities around
take the form of: the world. However, experience gained with the implementation
A general overview; of ICH Q7 since the approval in November 2000 shows that
Safetydetermination of PDEs for non-ICH Q3D uncertainties related to the interpretation of some sections exist.
elements/limits for other routes of administration/ Technical issues with regard to GMP of APIsalso in
context with new ICH Guidelinesneed to be addressed in
justication of higher limits/parenterals;
order to harmonize expectations during inspections.
Qualityrisk assessment processes/control strategy; Specic areas were identied for consideration arising from
Case studies. changes in requirements and expectations since Q7 was
In addition to material being produced by the IWG, Teasdale adopted in 2000, these included:
et al. published an article specically focused on the Imple- 1. Technical issuesincluding supply chain management
mentation of ICH Q3D Elemental Impurities Guideline: and the management of GMP within contract
Challenges and Opportunities.10 Within this the assessment manufacturing facilities. Key within this is which activities
of the drug substance was examined. Potential sources of EIs can be delegated and which cannot, seeking to clarify the
are illustrated in Figure 3. accountabilities within the quality assurance units within
Of the sources highlighted, the greatest risk comes from the customer organization.
intentionally added metals (e.g., metal catalysts used in the 2. The alignment of ICH Q7 to new guidelines (ICH Q8/
process). Q9/Q10/Q11), a specic concern being the variable
Although manufacturing equipment is a potential source of
interpretation of starting materials, i.e., the point of
EIs, in general control can be achieved through GMP, typically
introduction of GMP controls.
through conduct of an equipment compatibility assessment.
3. Changes to Process Validation requirements;
Indeed the most commonly used materials of construction such
4. Changes to Cleaning Validation requirements;
as Hastelloy, stainless steel, and glass, are selected due to their
specic chemical resistance. 5. Review of existing Q&As from training sessions and
Solvents used in the manufacture of drug substances are also conference documents, particularly information gathered
unlikely to represent a signicant risk of EI contamination. by Pharmaceutical Inspection Convention and Pharma-
Solvents are typically puried by distillation, and few involve ceutical Inspection Co-operation Scheme (jointly
the direct use of metal catalysts in their manufacture. referred to as PIC/S).
Overall it can be concluded that, while drug substance manu- This review relied on input not just from the 6 ICH parties
facturing often involves a complex series of processes, the risk of but also on input from other regions, e.g., Brazil, formal ICH
EI contamination is low. Indeed simple scientic principles can be observers including the WHO and key industry bodies
applied to clearly demonstrate that elemental impurity levels in including PIC/S.
the nal drug substance are controlled to appropriate levels. From the areas identied, some 19 dierent areas were
Table 2
question answer reflection
Should GMP ICH Q7 does not apply to steps prior to the introduction of the API In many ways the answer is self-explanatory; ICH Q7 does not apply
according to ICH Q7 starting material. However, there is an expectation that an appropriate to steps prior to the API starting material. What though is interesting
be applied for manu- level of controls suitable for the production of the API starting material is the comment that an appropriate level of control is required to
facturing steps before should be applied [ICH Q7, Section 1.3]. ensure the quality of the manufactured starting material. This cuts to
the defined API Normally, the API-starting material is defined in the regulatory filing by the heart of much of the current discussions around the definition of
starting material ? the applicant and approved in the regulatory reviewing process. starting materials and the need to ensure the quality of the starting
Additional guidance is provided to define and justify API starting material is maintained. It is likely therefore that primary within the
material derived from various sources [ICH Q11, Section 5]; for master controls expected prior to the starting material is effective change
cell banks, see [ICH Q5B; ICH Q5D]. management. Also of importance is cleaning and the effective control
of residues from other materials manufactured in the same facility.
When are dedicated ICH Q7 expects dedicated production areas for highly sensitizing materials What is in some ways most interesting is the absence of any direct
production areas ex- such as penicillins and cephalosporins because of the patient risk (e.g., reference to the recently published EMA shared facilities guideline.1
pected? anaphylactic shock in penicillin-allergic patients) from trace amounts of One obvious reason is that the guideline in question is specific to
these compounds in other medicines [ICH Q7, Section 4.40]. one region, i.e., Europe. It does though nevertheless still beg the
For materials of an infectious nature or high pharmacological activity or question, does the EMA guideline have any relevance to API
toxicity, a risk-based approach should be used to determine appropriate manufacture?
containment measures, which may include validated inactivation,
cleaning, and/or dedicated production areas [ICH Q7, Section 4.41].
While ICH Q7 does not define high pharmacological activity or toxicity,
these are generally determined by evaluating relevant animal and human
data collected during research and development. Important consid-
erations in this evaluation of pharmacological activity or toxicity may
include Occupational Exposure Limit (OEL), Permitted Daily Exposure
(PDE), Acceptable Daily Exposure (ADE), Threshold for Toxicological
Concerns (TTC), No Observed Adverse Effect Level (NOAEL) [ICH S
Guidelines, ICH E2E, Section 2.1.1], and the consequences of cross-
contamination [ICH Q9, Section 4.3].
What is expected in Different phrases are used to describe the expectation for evaluation of This again is an important question and answer in the context of Q11
terms of evaluation of suppliers of materials [ICH Q7, Sections 7.11, 7.12, 7.31], including and the definition of starting materials. A central concern of
suppliers of materials? traders, if any. [ICH Q7, Section 7.12] states that all materials are regulators is the lack of visibility/control of stages preceding starting
purchased against a specification and from suppliers approved by the materials. In practice many starting materials are likely to be supplied
quality unit [ICH Q7, Section 7.31]. Prior to approval of any supplier, an to the ultimate API manufacturer, and hence the points outlined are
evaluation should be conducted using a risk-based approach [ICH Q9, clearly germane to the management of SM suppliers and their
Appendix II.5; ICH Q7, Section 7.31]. More extensive evaluation is evaluation. It is certainly useful to see the Q&A document advocate a
needed for suppliers of those materials classified as critical [ICH Q7, risk based approach linked to criticality.
Section 7.11].
Can yield ranges de- Yes. Differing yield ranges [ICH Q7, Section 8.14] may be described and This would for example be a filter heel or drier heel. It should not be
fined for the first justified in the manufacturing procedure/master batch record explaining construed to mean that inadequate cleaning resulting in variable
batch differ from lat- the ranges [ICH Q7, Section 6.41]. For example, the first batch in the yield is in any way acceptable
ter batches within a series of production of batches of the same material (campaign) may
campaign? leave residual material in the equipment, resulting in a low yield in the
first batch and contributing to an increased yield in a subsequent batch of
the campaign.
Can the range of a No. However, information from the investigation into a process deviation There is a clear link here to the principles outlined in Q11. The overall
process parameter be (s) can be used to support expanding the range of a process parameter. theme is that changes need to be supported by good science.
expanded based only Additional work and studies are normally needed to adequately
on a process deviation demonstrate that the expanded range for the process parameter
(s)? consistently produces API of the necessary quality [ICH Q7, Sections
2.16, 12.11, 13.13].
Would additional proc- Any change in the API starting material should be assessed for impact on Again there is a clear correlation with the concepts outlined in Q11
ess validation studies be the API manufacturing process and the resulting API quality [ICH Q7, relating to API starting material. There should be sufficient
need- Section 7.14]. Additional validation studies of the API process may be understanding of the fate of impurities in the new SM. If more/
ed to support a change warranted if the change in the API starting material is deemed significant. different impurities carry through to the API, then validation would
in the source of an API In most cases, validation would be expected for a different source of the be expected.
starting material? starting material unless otherwise justified [ICH Q7, Sections 12.1,
13.13].
Is a retrospective ap- Prospective validation is normally expected for processes introduced since The most intriguing aspect of this is the point relating to redefinition
proach to validation the publication of ICH Q7. The concept of retrospective validation of a step as critical. One specific area where this may be envisaged in
still acceptable? remains acceptable as an exception for existing, well-established products is relation to the nonacceptance of a proposed SM. In such a
prior to the implementation of ICH Q7 [ICH Q7, Section 12.44]. scenario it is very likely that the applicant will have produced launch
stocks of the API, and yet the step in question if it precedes the
proposed SM will likely not have been validated. This might offer the
potential to retrospectively validate the step in question while
permitting the use of the existing launch stocks.
If regulatory discussions redefine a step as critical, which had previously
been considered noncritical, a protocol describing retrospective analysis
of data together with the commitment for concurrent or prospective
validation may be an option.
Regardless of the type of validation, the quality system should confirm the
ongoing robustness of the process (e.g., product quality review).
Is validation expected It depends. Recovery of material(s) from mother liquor is a process and the
for the recovery of need for validation should be assessed as for any other process step [ICH
material from mother Q7, Section 14.40]. Recovery of material from mother liquor in any
liquor? process step that must be controlled within predetermined criteria to
ensure the API meets its specification is, by definition, a critical process
step and should be validated. For example, recovery of API from mother
liquor would be considered a critical process step and should be validated
[ICH Q7, Sections 12.11, 12.12, 14.41, 14.43, 20see Glossary for
definitions of critical, materials, mother liquor, and validation].
E DOI: 10.1021/acs.oprd.5b00318
Org. Process Res. Dev. XXXX, XXX, XXXXXX
Organic Process Research & Development Regulatory Highlights
FDABeyondOurBordersForeignOces/EuropeanUnion/
AUTHOR INFORMATION UCM259808.pdf (accessed Oct 8, 2015).
(17) Impurities: Guideline for Residual Solvents Pde for Triethyl-
Corresponding Author amine and PDE of Methylisobutylketone http://www.ich.org/
*E-mail: andrew.teasdale@astrazeneca.com leadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/
F DOI: 10.1021/acs.oprd.5b00318
Org. Process Res. Dev. XXXX, XXX, XXXXXX